Adenovirus-Specific CD4+ T Cell Clones Recognizing Endogenous Antigen Inhibit Viral Replication In Vitro through Cognate Interaction

Heemskerk, Bianca; Vreeswijk, Tamara van; Veltrop-Duits, Louise A.; Sombroek, Claudia C.; Franken, Kees L. M. C.; Verhoosel, Renate M.; Hiemstra, Pieter S.; Leeuwen, Daphne van; Ressing, Maaike E.; Toes, René E. M.; Tol, Maarten J.D. van; Schilham, Marco W.

doi:10.4049/jimmunol.177.12.8851

Cited by 41 publications

(37 citation statements)

References 68 publications

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“…In addition to the role possibly played by CD8 þ lymphocytes, 10-12 the presence of CD4 þ T-lymphocytes may also be relevant to the final PML outcome, as this lymphocyte subset was shown to have a crucial role not only in providing helper functions, but also in exerting direct control in vivo of viral and tumor replication. [25][26][27] The observation that no GVHD flare occurred in our patient following donor JCV-specific CTL infusion, despite his previous severe chronic GVHD, confirms that the selection of virus-specific populations, through repeated rounds of antigenic-specific stimulation, efficiently depletes alloreactive T-lymphocytes. 15 The prognosis of PML is dismal after allogenic HSCT; in the last published review, it was reported to be fatal in five out of six HSCT patients and was associated with severe neurological sequelae in the only survivor.…”

Section: Discussionmentioning

confidence: 59%

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

Balduzzi

Lucchini

Hirsch

et al. 2010

Bone Marrow Transplant

108

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Progressive multifocal leukoencephalopathy (PML) associated with polyomavirus JC (JCV) infection has been reported to be usually fatal in allogeneic hematopoietic SCT (HSCT) recipients. We present the case of a 19-year-old HSCT patient diagnosed with JCV-associated PML after prolonged immunosuppression for severe GVHD. No short-term neurological improvement was observed after antiviral treatment and discontinuation of immunosuppressive therapy. Donor-derived JCV Ag-specific CTLs were generated in vitro after stimulation with 15-mer peptides derived from VP1 and large T viral proteins. After adoptive CTL infusion, virus-specific cytotoxic cells were shown in the peripheral blood, JCV-DNA was cleared in the cerebrospinal fluid and the patient showed remarkable improvement. Adoptive T-lymphocyte therapy with JCVspecific CTLs was feasible and had no side effects. This case suggests that adoptive transfer of JCV-targeted CTLs may contribute to restore JCV-specific immune competence and control PML in transplanted patients.

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Section: Discussionmentioning

confidence: 59%

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

Balduzzi

Lucchini

Hirsch

et al. 2010

Bone Marrow Transplant

108

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“…Cells were harvested and stained for cell surface markers, fixed, and permeabilized using a paraformaldehyde/saponin-based protocol, as previously described (27), and stained for intracellular IFN-g or perforin and granzyme B (Supplemental Table I). Because CD69 cannot be used as a discriminative marker in activated NK cells, the combination of CD56, CD54, and CXCR6 was used as an alternative for CD69-CXCR6 to define ltNK cells after in vitro stimulation.…”

Section: In Vitro Stimulation and Intracellular Stainingmentioning

confidence: 99%

Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population

Lugthart

Melsen

Vervat

et al. 2016

The Journal of Immunology

Self Cite

122

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Knowledge of human NK cells is based primarily on conventional CD56bright and CD56dim NK cells from blood. However, most cellular immune interactions occur in lymphoid organs. Based on the coexpression of CD69 and CXCR6, we identified a third major NK cell subset in lymphoid tissues. This population represents 30–60% of NK cells in marrow, spleen, and lymph node but is absent from blood. CD69+CXCR6+ lymphoid tissue NK cells have an intermediate expression of CD56 and high expression of NKp46 and ICAM-1. In contrast to circulating NK cells, they have a bimodal expression of the activating receptor DNAX accessory molecule 1. CD69+CXCR6+ NK cells do not express the early markers c-kit and IL-7Rα, nor killer cell Ig-like receptors or other late-differentiation markers. After cytokine stimulation, CD69+CXCR6+ NK cells produce IFN-γ at levels comparable to CD56dim NK cells. They constitutively express perforin but require preactivation to express granzyme B and exert cytotoxicity. After hematopoietic stem cell transplantation, CD69+CXCR6+ lymphoid tissue NK cells do not exhibit the hyperexpansion observed for both conventional NK cell populations. CD69+CXCR6+ NK cells constitute a separate NK cell population with a distinct phenotype and function. The identification of this NK cell population in lymphoid tissues provides tools to further evaluate the cellular interactions and role of NK cells in human immunity.

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“…Since HAdV-specific CD4 + T cells are capable of directly lysing HAdV-infected target cells, the relative contribution of HAdV-specific CD4 + and CD8 + T cells in protection against HAdV disease after allogeneic SCT remains to be elucidated. 21,22 For the generation of donor-derived HAdV-specific T-cell lines for clinical application, peripheral blood has been stimulated with HAdV antigens or HAdV-transduced antigenpresenting cells, resulting in enrichment of either CD4 + or CD8 + T cells specific for HAdV. 20,[23][24][25][26][27][28][29] Although alloreactivity was reduced using these strategies, the frequency of HAdVspecific T cells in the cell lines was not determined or was limited, even when interferon (IFN)γ-based isolation steps were included.…”

Section: Introductionmentioning

confidence: 99%

Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection

Zandvliet¹,

Falkenburg²,

Liempt³

et al. 2010

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundHuman adenovirus can cause morbidity and mortality in immunocompromised patients after allogeneic stem cell transplantation. Reconstitution of adenovirus-specific CD4 + T cells has been reported to be associated with sustained protection from adenovirus disease, but epitope specificity of these responses has not been characterized. Since mainly CD4 + T cells and no CD8 + T cells specific for adenovirus have been detected after allogeneic stem cell transplantation, the relative contribution of adenovirus-specific CD4 + and CD8 + T cells in protection from adenovirus disease remains to be elucidated. Design and MethodsThe presence of human adenovirus hexon-specific T cells was investigated in peripheral blood of pediatric and adult allogeneic stem cell transplant recipients, who showed spontaneous resolution of disseminated adenovirus infection. Subsequently, a clinical grade method was developed for rapid generation of adenovirus-specific T-cell lines for adoptive immunotherapy. ResultsClearance of human adenovirus viremia coincided with emergence of a coordinated CD8 + and CD4 + T-cell response against adenovirus hexon epitopes in patients after allogeneic stem cell transplantation. Activation of adenovirus hexon-specific CD8 + and CD4 + T cells with a hexon protein-spanning peptide pool followed by interferon-γ-based isolation allowed rapid expansion of highly specific T-cell lines from healthy adults, including donors with very low frequencies of adenovirus hexon-specific T cells. Adenovirus-specific T-cell lines recognized multiple MHC class I and II restricted epitopes, including known and novel epitopes, and efficiently lysed human adenovirus-infected target cells. ConclusionsThis study provides a rationale and strategy for the adoptive transfer of donor-derived human adenovirus hexon-specific CD8 + and CD4 + T cells for the treatment of disseminated adenovirus infection after allogeneic stem cell transplantation.Key words: allogeneic stem cell transplantation, adoptive immunotherapy, adenovirus infection, adenovirus-specific T cells.Citation: Zandvliet ML, Falkenburg JH, van Liempt E, Lankester AC, Kalpoe JS, Kester MG, van der Steen DM, van Tol MJ, Willemze R, Guchelaar HJ, Schilham MW, and Meij P. Combined CD8 + and CD4 + adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection. Haematologica 2010;95(11):1943-1951. doi:10.3324/haematol.2010

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Adenovirus-Specific CD4+ T Cell Clones Recognizing Endogenous Antigen Inhibit Viral Replication In Vitro through Cognate Interaction

Cited by 41 publications

References 68 publications

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

Polyomavirus JC-targeted T-cell therapy for progressive multiple leukoencephalopathy in a hematopoietic cell transplantation recipient

Human Lymphoid Tissues Harbor a Distinct CD69+CXCR6+ NK Cell Population

Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection

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